This invention relates to anti-cancer agents and processes for their preparation. More particularly, it relates to anti-cancer agents which are bis(bioreductive) alkylating agents.
Several known anti-cancer agents having a quinone nucleus owe their antineoplastic properties to their ability to interact with desoxyribonucleic acid (DNA). For example, the mechanism of action of antitumor mitomycins is believed to involve in vivo enzymatic reduction of the quinone nucleus with consequent generation of reactive quinone methides capable of alkylating DNA, ribonucleic acid (RNA) and other biological macromolecules; see, inter alia:
Kennedy et al, Fed. Am. Soc. Exp. Biol., 38,443 (1979); and
Proc. Am. Assoc. Cancer Res., 20, 278 (1979). Some of the antitumor agents seem to act as bifunctional alkylators which add to both strands of the DNA double helix, thereby causing cross-linking; see:
Iyer et al, Proc. Natl. Acad. Sci. U.S., 50, 355 (1963).
It is also known that certain bifunctional alkylators not requiring bioreductive activation are more effective than their monofunctional counterparts; see, inter alia:
Pelaprat et al, J. Med. Chem., 23, 1336 (1980); Gaugain et al, Biochemistry, 17, 5071 (1978); and Neidle, in Ellis and West (eds.), Progress in Medicinal Chemistry, 16, 151-221 (Elsevier/North-Holland Biomedical Press, Amsterdam, 1979).
However, according to:
Lin et al, J. Med. Chem., 19, 1336 (1976) when two alkylating chains are bonded to the same quinone ring, the bifunctional alkylators are no more efficient than the corresponding monofunctional alkylators.
After careful consideration, we concluded that the failure of the Lin bifunctional alkylators to show activity greater than that of the corresponding monofunctional alkylators might be due to an improper spacing between the two alkylating groups and accordingly that better results might be obtained using bifunctional alkylators in which a spacer region is interposed between two quinone alkylating moieties. Accordingly, we have now synthesized certain compounds of this type and found that they exhibit highly desirable antitumor activity in animal tests.